Activation of p70S6 Kinase-1 in Mesenchymal Stem Cells Is Essential to Lung Tissue Repair.

Abstract

All-trans retinoic acid (ATRA) or mesenchymal stem cells (MSCs) have been shown to promote lung tissue regeneration in animal models of emphysema. However, the reparative effects of the combination of the two and the role of p70S6 kinase-1 (p70S6k1) activation in the repair process have not been defined. Twenty-one days after intratracheal instillation of porcine pancreatic elastase (PPE), MSC and/or 10 days of ATRA treatment was initiated. Thirty-two days later, static lung compliance (Cst), mean linear intercepts (MLIs), and alveolar surface area (S) were measured. After PPE, mice demonstrated increased values of Cst and MLI, and decreased S values. Both ATRA and MSC transfer were individually effective in improving these outcomes while the combination of ATRA and MSCs was even more effective. The combination of p70S6k1-/- MSCs transfer followed by ATRA demonstrated only modest effects, and rapamycin treatment of recipients with wild-type (WT) MSCs and ATRA failed to show any effect. However, transfer of p70S6k1 over-expressing-MSCs together with ATRA resulted in further improvements over those seen following WT MSCs together with ATRA. ATRA activated p70S6k1 in MSCs in vitro, which was completely inhibited by rapamycin. Tracking of transferred MSCs following ATRA revealed enhanced accumulation and extended survival of MSCs in recipient lungs following PPE but not vehicle instillation. These data suggest that in MSCs, p70S6k1 activation plays a critical role in ATRA-enhanced lung tissue repair, mediated in part by prolonged survival of transferred MSCs. p70S6k1-activated MSCs may represent a novel therapeutic approach to reverse the lung damage seen in emphysema. Stem Cells Translational Medicine 2018;7:551-558.

• Authors: Katsuyuki Takeda, Fangkun Ning, Joanne Domenico, Masakazu Okamoto, Shigeru Ashino, Sang-Ha Kim, Yi Yeong Jeong, Yoshiki Shiraishi, Naohiro Terada, Everett Rand Sutherland, Erwin W Gelfand
• Journal: Stem cells translational medicine (Stem Cells Transl Med) Vol. 7 Issue 7 Pg. 551-558 (07 2018) ISSN: 2157-6564 [Print] England
• PMID: 29730892 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Chemical References

• Tretinoin
• Ribosomal Protein S6 Kinases, 70-kDa
• ribosomal protein S6 kinase, 70kD, polypeptide 2
• Pancreatic Elastase

Topics

• Animals
• Bone Marrow Cells (cytology)
• Disease Models, Animal
• Female
• Lung (physiology)
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (cytology, drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Pancreatic Elastase (toxicity)
• Phosphorylation
• Pulmonary Emphysema (etiology, therapy)
• Regeneration
• Ribosomal Protein S6 Kinases, 70-kDa (genetics, metabolism)
• Tissue Engineering
• Tretinoin (pharmacology, therapeutic use)